3273

7a,7'a-Bis(l-methyl-3-oxoprop-l-eno)-6,14-end~ethenotetraAnal. Calcd for C2J-L9N04: C, 75.8; H, 6.6. Found: C,

hydrothebaine. Repeated chromatographic purification of the
75.6; H , 6.5.
ketol XVI on alumina plates in ether solution led to the isolation
In a similar manner, the following ketones were prepared in
also of a small quantity of a new base, mp 234", vmX 1690 cm-I.
poor yield from 0- and p-tolylmagnesium bromide: 6,14-endoThis was also obtained by heating the ketol (70 mg) with 98-100z
etheno-7a-(2-methylbenzoyl)tetrahydrothebaine(prisms, mp 223 O ,
formic acid (1 ml) at 100" for 10 min. The solution was diluted
vmax 1690 cm-1. Anal. Calcd for C29H31NO4: C, 76.1; H ,
with water, basified with ammonia, and extracted with ether, when
6.8. Found: C, 75.7; H, 7.1); 6,14-endo-etheno-7a-(4methylthe unsaturated ketone (50 mg) was obtained as white prisms, mp
benzoy1)tetrahydrothebaine (prisms, mp 196", vmax 1690 cm-1.
A m / . Calcd for C29H31N04: C, 76.1; H, 6.8. Found: C,
234", from methanol.
75.8; H, 6.7).
Anal. Calcd for C46HS2N207:C, 74.2; H, 7.0. Found: c,
7a,7'a-Bis(l-hydroxy-1-methyl-3-oxopropano)-6,14-endo-etheno- 74.0; H, 7.1.
tetrahydrothebaine (IX, R = H). 'Ia-Acetyl-6,14-endo-ethenoCharge-Transfer Complex, Thebaine Methiodide-Benzoquinone.
tetrahydrothebaine (11, R = Me) (5 g) in anhydrous benzene (20
Thebaine methiodide (5 g) and benzoquinone (1.5 g) were heated on
ml) was added with vigorous stirring to a solution of anhydrous
the water bath in chloroform (25 ml) until separation of an orange
magnesium iodide (3.6 g) in ether (50 ml) and benzene (20 ml) at
crystalline solid began. The mixture was cooled, and the orange
room temperature. A white precipitate formed almost immedicomplex was collected (5.0 g), mp 205-206", on rapid heating (1it.l'
ately. After 15 min the mixture was decomposed by the addition
mp 205 ").
of aqueous ammonium chloride. The ether-benzene layer was
Reduction of Complex. A solution of sodium borohydride (0.1
separated, dried, and evaporated, when a viscous gum was obtained.
g) in water (2 ml) was added to a warm stirred solution of the comChromatographic separation of this product on silica plates using
plex (1 g) in ethanol (15 rnl). A transient violet color developed,
a system of a 7: 4: 1 mixture of ethyl acetate, 2-propanol, and water
and the solution rapidly became almost colorless. On cooling the
showed it to contain three components in the ratio of approximately
solution, thebaine methiodide (0.6 g), mp 224", was recovered, and
3: 6: 1 . Preparative plate chromatography using the same system
on filtration and dilution of the solution with dilute ammonium
afforded specimens of the two major components. The component
chloride hydroquinone (0.12 g), mp 170", was obtained.
with greatest Ri value (30z)was identified as 7a-acetyl-6,14-endoSimilar results were obtained when the complex in aqueous
ethenotetrahydrothebaine (11, R = Me). The 60% component
ethanol was reduced with sulfur dioxide.
(intermediate Ri value) was obtained as off-white prisms, mp
150-151 ', from methanol, vmax 1715 and 3490cm-1, andwas identiAcknowledgments, The authors wish to thank Dr.
bis( 1-hydroxy- 1methyl- 3-oxopropano)-6,14-endo-ethfied as 7a,7 'aD. E. Webster of the University of Hull, England, for
enotetrahydrothebaine (IX, R = H).
the determination of nmr spectra, Mr. A. C. Young
Anal. Calcd for C46HS4N?O~:
C, 72.4; H, 7.1. Found: C,
72.3; H, 7.0.
for chromatographic studies on thin and thick layer
Separation of this ketol was also achieved on alumina plates
plates, and the following for experimental assistance:
using ether as solvent, and from these plates the minor component
Mr. J. Fulstow, Mr. J. F. Saville, Mr. N. M. Scollick,
(1Oz) was also isolated. This has been identified as a product of
E. W. Walker, Mr. G. R. Young, and the late
Mrs.
rearrangement of the ketone I1 (R = Me) and is described in detail
Mr. S . R. Duff.
in another publication?

Novel Analgesics and Molecular Rearrangements in the

Morphine-Thebaine Group. 11.' Alcohols Derived from
6,14-endo-Etheno-and 6,14-endo-Ethanotetrahydrothebaine
K. W. Bentley, D. G . H a r d y , and B. Meek
Contributionf r o m the Research Laboratories, Reckitt and Sons Lid.,
Kingston-upon-Hull, England. Receiced Septem ber 26,1966

Abstract: A series of secondary and tertiary alcohols have been prepared by the reduction and reaction with Grignard
reagents of the aldehyde I (R = H), the ketones I (R = Me, Et, n-Pr, and Ph), and their 6,14-ethano analogs. The
stereospecificity of the reactions is explained. In this way analgesics of very high potency, up to 500 times that of
morphine, have been obtained.

he high analgesic activity of the ketone I (R = Me)

and its C-7 epimer, reported in the preceding paper,
contrasts with the inactivity of the related esters I
(R = OMe or OEt). The effects on the activity of further modifications of the keto group, involving removal
of the electron deficiency at the carbon atom, were accordingly studied. Reduction of the ketone I (R =
Me) with aluminum isopropoxide affords a product
consisting of 9 5 % of one isomer of the secondary
alcohol I1 (R = H, R' = Me), whereas reduction with

(1) (a) Part I : K. W. Bentley and D. G. Hardy, J . Am. Chem. SOC.,89,

3267 (1967). (b) A preliminary report of part of this work has been made
by K. W. Bentley and D. G. Hardy, Proc. Chem. SOC.,220 (1963). (c)
This work is covered by British Patent 925,723.

sodium borohydride yields an approximately 1 : 1

mixture of this and the diastereoisomeric alcohol I1
(R = Me, R' = H), which was resolved into its components by preparative thin layer chromatography.
Since there is more or less free rotation about the bond
linking the carbonyl group to C-7, both sides of this
group are almost equally accessible to attack by a hydride ion, but in the Meerwein-Pondorff reduction,
which proceeds through hydrogen transfer in a cyclic
transition state,2 steric hindrance in the transition state
results in the preferential transfer of hydrogen t o one
(2) L. M. Jackman, A . K. Macbeth, and J. A. Mills, J . Chem. SOC.,
2641 (1949).

Bentley, Hardy, Meek / Alcohols Derived from 6,14-Ethano Analogs

3274

side of the carbonyl group. The examination of models

of such a six-membered transition state (see below)
shows that steric hindrance is least in the arrangement
that leads t o the alcohol I1 (R = H,R 1= Me).
An excess of methylmagnesium iodide converts the
ketone I (R = Me) in high yield into the tertiary alcohol I1 (R = R = Me), which is also readily prepared
from the esters I (R = OMe or OEt), and the nmr
spectrum of this alcohol shows that the stereochemical
disposition of groups at C-7 is the same as that in the
parent ketone.3a The tertiary alcohol epimeric at C-7
with I1 (R = R = Me) was prepared in the same way
from the 7 p isomer of the ketone I (R = Me). The
carbinols prepared in this way were all found to be potent analgesics. Accordingly, the variation in analgesic
activity within a series of alcohols of general structure
I1 was studied, and during the course of this work many
compounds were obtained with analgesic activities
never previously approached in the morphine series, in
which hitherto the most active members have been
14-acetoxydihydrocodeinone and 5methyldihydromorp h i n ~ n e ,both
~
of which are about 12 times as active
as morphine.

cases);6a (d) Grignard reduction to give the diastereoisomeric secondary alcohol 11 (R = H) (minor reaction); and (e) base-catalyzed rearrangement of the
ketone followed by Grignard reaction at the carbonyl
group (minor reaction). Of these processes the basecatalyzed rearrangement is of minor importance and
will be discussed in detail together with other topics
in a subsequent communication.6b
The normal Grignard reaction in this series shows a
remarkably high degree of stereoselectivity, and in
those cases in which Grignard reduction does not
compete with the normal reaction a high yield of an
almost pure diastereoisomer of the tertiary carbinol
is obtained. For example, the ketone I (R = Me)
with phenylmagnesium bromide afforded almost entirely the alcohol I1 (R = Me, R = Ph), whereas the
diastereoisomeric alcohol I1 (R = Ph, R = Me) was the
almost sole product of the action of methylmagnesium
iodide on the phenyl ketone I (R = Ph). The presence
of a trace of the second isomer in the product in each
case was demonstrated by thin layer chromatography.
The stereochemical assignments of structures t o these
isomeric carbinols, at first tentatively made after a study
of models, were rigorously confirmed by nmr spectroscopic studies.3a
Similarly the tertiary carbinol I1 (R = Me, R =
n-Pr), resulting from the normal Grignard reaction
of n-propylmagnesium iodide with the methyl ketone
I (R = Me), is diastereoisomeric with the principal
product I1 (R = n-Pr, R = Me) of the interaction of
methylmagnesium iodide and the n-propyl ketone I
(R = n-Pr). The seat of the isomerism was clearly
shown in this case to be the alcoholic group since both
carbinols were dehydrated t o the same olefin 111, which
gave propionaldehyde on o z o n ~ l y s i s . ~The structure
of the carbinol I1 (R = Me, R = n-Pr) has been confirmed by X-ray crystallographic analysis of the hydrobromide.3b
Grignard reduction is, where possible, a process
seriously competitive with the normal Grignard reaction, and in some cases accounts for up to 30% of the
total product. Like the normal reaction, it shows a
remarkably high degree of stereoselectivity, and the
product consists almost entirely of the alcohol I1 (R
= H),though the presence of about 5 % of the diastereoisomer I1 (R = H)can be detected on thin layer chromatographic plates. Both the Grignard and Meerwein-Pondorff reduction processes are generally believed t o proceed by hydrogen transfer in similarly constituted transition
IV and V, and might thus
in the case of the ketone I (R = Me) be expected t o lead
to the same product. This expectation is not borne
out in practice.
Grignard reduction of the ketone with n-propyl- or
isobutylmagnesium halides affords the secondary alcohol diastereoisomeric with that obtained in the
Meerwein-Pondorff reduction, and identical with the

Meon
I1

Me0
C4

t!CHs

Et
111

The alcohols of general structure I1 were prepared

by the action of Grignard reagents or lithium alkyls
on the aldehyde I (R = H),the ketones I (R = Me,
Et, n-Pr, and Ph), and the ester I (R = OEt). The
reactions of the ketones I with Grignard reagents
RMgX are generally complex and lead to the formation
of a number of products resulting from the following
processes: (a) normal Grignard reaction with RMgX
to give the tertiary carbinol I1 (major reaction); (b)
normal Grignard reaction with RMgX to give the
tertiary alcohol diastereoisomeric with I1 (minor reaction); (c) Grignard reduction where possible, i.e.,
when R contains a ,&hydrogen atom, t o give the secondary alcohol I1 (R = H)(major reaction in many
(3) (a) W.Fulmor, J. E. Lancaster, G. 0. Morton, J. J. Brown, C. H.
Howell, C. T. Nora, andR. A. Hardy, Jr., J. Am. Chem. SOC.,89, 3322
(1967); (b) J. H. van den Hende and R. Nelson, private communication;
J . Am. Chem. SOC.,89,2901 (1967).
(4) R. E. Lutz and L. F. Small, J . Org. Chem., 4, 220 (1939).
(5) L. F. Small, H. M. Fitch, and W. E. Smith, J . Am. Chem. SOC.,
58, 1457 (1936); G. Stork and L. Bauer, ibid., 75, 4373 (1953).

Journal of the American Chemical Society

89:13

(6) (a) This reaction was first reported to us by C. F. Howell, J. J .

Brown, W. Fulmor, G. 0. Morton, and R. A. Hardy, Jr., of Lederle
Laboratories, Pearl River, N. Y . ,whom we thank also for much helpful
discussion of the mechanisms of the reaction of the ketones I with
Grignard reagents. (b) Part VI: I<. W. Bentley, D. G. Hardy, H. P.
Crocker, D. I. Haddlesey, and P. A. Mayor, J . Am. Chem. SOC.,89, 3312
(1967).
(7) Part IV: K. W. Bentley, D. G. Hardy, and B. Meek, ibid., 89,
3293 (1967).
( 8 ) M. S. Kharasch and 0. Reinmuth, Grignard Reactions of NonMetallic Substances, Constable and Co. Ltd., London, 1954,p 147.

/ June 21, 1967

3275

IV

second component of the product of reduction of the

ketone with sodium borohydride. If the MeerweinPondorff reduction leads, as postulated above, to the
alcohol I1 (R = H, R = Me), the product of Grignard
reduction must have the structure I1 (R = Me, R
= H), and these structural assignments have been
confirmed in the following way. The MeerweinPondorff reaction product in chloroform solution
shows hydroxyl absorption at 3504 cm-1, indicating
strong hydrogen bonding between the hydroxyl and the
spatially proximate C-6 methoxyl group, which results
in an arrangement involving disposition of the hydrogen
atom in the carbinol system of the alcohol I1 (R = H,
R = Me) downward toward the 6,14-etheno bridge.
In agreement with such a representation, in which steric
hindrance of the etheno bridge is minimal, this alcohol
is very readily hydrogenated at room temperature and
pressure. Hydrogen bonding of a similar kind in the
isomeric alcohol I1 (R = Me, R = H) would, however,
involve disposition of the larger CH3 group downward toward the etheno bridge, and this would be expected to result in some hindrance to hydrogenation of
the bridge and also to a weakening of the hydrogen
bond or even to the establishment of an alternative
arrangement with a weak bond between the hydroxyl
group and the T orbitals of the etheno bridge. In
agreement with this, the Grignard reduction product
of the ketone I (R = Me) is resistant to hydrogenation
at room temperature, and shows hydroxyl absorption
at 3540 cm- (weaker hydrogen bond than in the isomeric carbinol) and also at 3605 cm-I (feeble bond to
the etheno bridge)
Thus, both Grignard reaction with and Grignard
reduction of the ketone I (R = Me) afford products
belonging to the same stereochemical series I1 (R =
Me). This asymmetric induction may be explained
on the basis of a model similar to those outlined by
Cram and his co-workers.9 If the Cram five-membered
transition state is replaced in this series by a six-membered intermediate in which a complex is formed by
coordination of the magnesium atom with oxygen
atoms of both C-7 carbonyl and C-6 methoxyl groups
(thus completing the outer electron shell of the magnesium), then an inspection of models shows that
top-side approach of the group R to the carbonyl
carbon, as depicted in VI, leading to VI1 is much less
hindered than approach from below (the vicinity of the
6,14-etheno bridge). In the same complex, if the group
R is one in which /3-hydrogen transfer can occur then
Grignard reduction (VIII) would lead to alcohol IX
[identical with the complete structure I1 (R = Me, R
= H)] belonging t o the same stereochemical series as
the products of the normal reaction.
In the Meerwein-Pondorff reduction, however, the
aluminium atom can complete its valency shell by co(9) D. J. Cram, F. Ahmed, and A. Elhatez, J . Am. Chem. SOC.,74,
5828 (1952).

il cH3

VI

dH3
VI1

dH3
VI11

CH3
IX

ordination with the carbonyl oxygen atom alone, and

the establishment of a more rigid cyclic arrangement
involving the C-6 methoxyl group is not necessary. In
such a case, free rotation about the carbonyl-C-7 bond
is still possible and hydrogen transfer in the complex
would be expected to occur with the groups in the disposition involving least steric hindrance. This arrangement is that in which the coordinated carbonyl group is
most remote from the group with the greatest effective
size, namely the C-6 methoxyl group. This arrangement is shown in part structure X, which is a Newman
projection of part of the ketone I (R = Me) looking
along the line of the carbonyl-C-7 bond, and least
hindered hydrogen transfer to the carbonyl group would
occur as shown, from above, to give the secondary
alcohol XI which is identical with XII. This alcohol
is diastereoisomeric with that obtained by Grignard
reduction, and is represented in full by structure
I1 (R = H, R = Me).
Me2

XI

Ik

CH3
XI1

The reaction of the ketone I (R = Me) with lithium

alkyls involves, in the cases studied, more base-catalyzed
rearrangement than does the reaction with Grignard
reagents, but this still remains a minor side reaction
(<lo%), and the formation of tertiary carbinol is
somewhat less stereoselective. Secondary alcohol formation is not observed, however, and in those cases in
which Grignard reduction is troublesome the use of the
corresponding lithium alkyl is to be preferred.

Bently, Hardy, Meek J Alcohols Derived from 6,14-Ethano Analogs

3276
Table I. Alcohols of Structure I1
MP,

R
H
Me
H
H
H
H
H
H
H

Me
H
Et
n-Pr
11- C8H 17
Ph
CHsPh
CHSCHzPh
(CHd30Et
(

-0

H
Me
Me
Et
Me
n-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me

Me
Et
Me
n-Pr
Me
i-Pr
n-Bu
i-Bu
t-BU
ti-Am
i-Am
t-Am

n-CsH18
tl-C7Hi,j
n-CsH17
Ph
Me
CHzPh
(CHzhPh
(CHMh
0-Tolyl
p-Tolyl
CHZC~H~F-p
CHzC6HaCI-p
CHzCsH40Me-p
CHn=CHPh
CH=CHz
CECH
CHPCH=CH~
Cyclohexyl
Cyclopentyl
(CHzIzOEt
(CHdzOPh

Me

(CHh

Me

C H Z G

Et
Et
n-Pr
Il-BU
CHPPh
Ph
Ph
Ph
Ph
Ph
a

Morphine

Et
Ph
ti-Pr
n-Bu
CHzPh
Ph
n-Pr
CHzPh
Cyclohexyl
CH*CH=CHz
=

1.

Hydrobromide.

Comoosition

82
81

Calcd,
C
H

Found,
C
H

MP,
C,
HCl
210
240
90b
176c
15Y

Molar
potency
1 .o
0.9
0.8
5.3
0.2
0.01
1.6
80
12

72.1
72.1
54.3
56.5
74.9
75.4
15.8
76.0
56.9

7.6
7.6
7.1
7.1
8.9
7.1
7.2
7.4
7.5

72.0
71.8
54.6
56.4
74.6
75.6
15.6
75.6
56.8

7.5
8.0
7.1
7.1
8.6
7.1
7.3
7.4
7.2

114

69.8

8.2

70.0

8.1

98

74.4

8.3

74.1

8.3

7.9
8.1
8.1
8.2
8.2
8.2
8.4
8.4
8.4
8.6
8.6
8.4
8.7
8.6
9.1
7.2
7.2
7.4
1.6
8.0
1.4
7.4
7.0
6.1
7.5
7.1
1.6
7.1
7.8
8.4
8.2
8.5
7.8

72.5
72.9
72.9
73.3
73.2
73.0
73.9
73.8
73.8
73.8
74.0
63.8
62.7
65.0
75.3
15.5
75.6
76.1
76.1
72.5
76.1
76.0
73.0
70.7
11.8
71.2
73.3
73.6
73.6
74.8
74.3
66.3
73.1

7.7
8.1
8.2
8.2
8.4
8.3
8.4
8.6
8.5
8.4
8.4
8.2
8.7
8.6
8.9
7.2
7.2
7.3
7.8
7.9
7.3
7.4
7.3
6.9
7.3
6.9
7.6
7.2
7.8
8.3
8.0
8.3
7.5

221
245

2.7
20

217

96

208
152
187
146
94
239
197
148
180
117
92
155
186
160
20 1
86
107
221

72.5
73.1
73.1
73.3
73.3
73.3
73.8
73.8
13.8
74.1
74.1
64.0
63.0
64.9
75.5
75.8
75.8
76.1
76.4
72.3
76.1
76.1
73.3
70.9
71.6
71.2
73.3
73.7
73.6
74.8
74.6
66.5
73.3

260
202
240
248
260

1.5
4.0
1.4
0.2
0.41
59
1 .o
6.0
0.05

128

72.5

8.6

72.6

8.4

185

92

140

71.1

8.1

71 .O

8.0

152
166
209

13.3
76.1
14.2
61.1
78.7
78.2
76.5
78.5
77.6
76.6

8.1
7.4
8.7
7.9
7.2
6.7
7.6
6.9
7.8
7.2

73.0
76.2
73.9
61.2
78.5
77.9
76.2
78.3
77.3
76.5

8.0
7.4
8.7
7.8
7.2
6.7
7.6
7.0
7.9
7.0

...

...
78
210
95
80

...

166
74 (132)
165
176
148
165
150
150
216
103
126
...
. I .

...
, . .

...

190
220
177
210
232
21 7

12S
166
1ooc

24
9.0

218
188
250
258
188
270
256
262
194
230
236
235
190
250

248

10
24
2.5
0.1
15
30
0.6
2.0
1.2
0.3
0.07
0.09
150
500
2.1
0.15
0.10

130

2.5

186
6ZC
190
266
210
220
239

3.1
3.0
0
0
0.2
0

0.04
0.53

Bitartrate.

The alcohols of general structure I1 prepared in this

way are listed, together with their analgesic potencies,
in Table I. The analgesic activities were determined by
the tail pressure method in rats, with administration of
the
in
as their
aqueous solution by the subcutaneous route, and this
Journal of the American Chemical Society / 89:13

work will be reported in detail elsewhere, together with

the results of other pharmacological studies. lo The
highest activities are observed in those alcohols in which
there is a moderate disparity in size between R and R,
(10) Some details are briefly given by R. E. Lister, J . Pharm. Pharmacol., 16,364 (1964).

June 21, 1967

3277

and in homologous series in which the group R remains

constants as a hydrogen atom or a methyl group peak
activity is reached when R ' has a size equivalent to that
of a three to five carbon chain, and further lengthening
of the chain results in a steady decrease in activity.
The preferred constant substituent R is a methyl
group, and the most potent analgesic in this series is the
alcohol I1 (R = Me, R ' = CH2CH2Ph).
The alcoholic hydroxyl group of the secondary
alcohols was rcadily esterified, but this modification has
little effect on the analgesic potency. The tertiary
alcohols, however, are very resistant to esterification.
The two diastereoisomeric secondary alcohols I1 (R
= H, R ' = Me and R = Me, R ' = H) were esterified
with phenylglyoxalyl chloride and, following Prelog's
method,I1 the resulting esters were treated with methylmagnesium iodide and the products hydrolyzed to
atrolactic acid. With the alcohol I1 (R = H, R' =
Me), the three conformations of the phenylglyoxalyl
ester are XIII, XIV, and XV, in which 0 represents the
tetrahydrothebaine unit, and in these the size of groups
is in the order 0 > Me > H and, as in the cases studied
by Prelog, attack by the Grignard reagent on XI11
would be from below and on XIV and XV would be
from above. However, the examination of models of

0
XI11

XIV

xv

XVI

base and the methylation of other tertiary alcohols in

the series proved unsuccessful.
Catalytic reduction of the tertiary alcohols was in all
cases achieved only at elevated temperature and pressure. Hydrogen bonding between the hydroxyl and
C-6 methoxyl groups results in conformations in
which one or the other of the alkyl groups R and R '
in structure 11 is disposed in the direction of the 6,14etheno bridge, with consequent hindrance of the approach of this bridge to the catalyst surface. Reduction is achieved over Raney nickel catalyst at 160-170"
(200 atm) to give bases of general structure XIX. These
6,14-etheno alcohols are also preparable from the
6,14-ethano ketone XX which is obtained from the
etheno ketone I (R = Me) by reduction under milder
conditions. The effect of the COCH3 group in the
ketone I (R = Me) in shielding the etheno bridge is
much less than the effect of the alcoholic group in the
hydrogen-bonded alcohols 11, and since the shielding
effect on the etheno bridge of the smaller CHO group
is even less than that of the COCH3 group, the aldehyde
I (R = H) can be reduced under even milder conditions.
In the 7P-acetyl compound, the COCH, group is disposed on the side of the molecule opposite to the etheno
bridge, hydrogenation of which is accordingly unhindered, and this base can be rapidly reduced at room
temperature. The Grignard reaction with the 6,14ethano ketone XX in general follows the same pattern
as that with the etheno analog I1 (R = Me), giving rise
to tertiary carbinol XIX, secondary carbinol as a result
of Grignard reduction, and base-catalyzed rearrangement. Base-catalyzed rearrangement is generally more
important in this than in the etheno series, and on
occasions accounts for up to 3 0 x of the product.6b
The normal Grignard reaction displays the same stereospecificity as in the 6,14-etheno series. The 6,14-ethano
alcohols XIX prepared by these methods are listed in
Table 11.

Meom
XVII

XVIII

these three conformations reveals that nonbonded

interactions are very much less in the form represented
by XI11 than in the other two, and the ester would be
expected to adopt predominantly this form, attack of
which by the Grignard reagent would lead, after hydrolysis, t o an excess of (+)-atrolactic acid. With the
ester from the diastereoisomeric alcohol I1 (R = Me,
R ' = H) the conformation XVI would be expected t o
be heavily favored over XVII and XVIII, and the same
process with this ester would be expected to lead t o an
excess of (-)-atrolactic acid. In this event this sequence
of reactions on the alcohol obtained by MeerweinPondorff reduction of the ketone I (R = Me) gave
atrolactic acid, [CY]*~D+4.8 O, whereas the product of
Grignard reduction of the ketone in the same way
afforded atrolactic acid, [ c Y ] ~ O D -5.4", and these results
support the structures assigned above to these bases.
0-Alkylation of the tertiary alcohols was also very
difficult, but the base I1 (R = R ' = Me) was methylated
with potassamide and methyl iodide in liquid ammonia
to its methyl ether. Other attempted alkylations of this
(11) V. Prelog, Helc. Chim. Acta, 36, 308 (1953).

OHC\CH3

xx

XIX

w
I

.,Me

As in the parent Diels-Alder adducts I (R = Me and

OEt), quaternary salt formation with the alcohols I1
proceeded only very slowly, good yields being obtained
only after several days under reflux with methyl iodide
in acetone. In the cases examined, Hofmann degra-

Bently, Hardy, Meek

1 Alcohols Deriaed from 6,14-Ethano Analogs

3278
Table 11. Alcohols of Structure XIX

R'

H
Me
Me
Et
n-Pr
i-Pr

H
Me
Me
Me
Me
Me
Me
Me
Me
Me

/l-Bu

sec-Bu
i-Bu

t-Bu
n-Am
i-Am
CHZPh

Me
Me
Me

Me
Morphine

Mp,
"C

124
51
142
146
187
158
147
164
170
188
113
126
146
202
195

Comuosition

-C Calcd, % H--

CdLsN04
71.1
C2aHziN04
71.6
C24HauN04
72.1
C2jHajNOa
72.6
CIBHKNO~
73.1
CuH37N04
73.1
GH3rjN04
73.4
C-xHa'~N04
73.4
CziHasNOa
73.4
C2iHuN04
73.4
C ~ ~ I N O ~ 73.8
C?~H.iiN04
73.8
CmHxN04
75.8
C23H36N04
75.5
G&iN04

74.5

---Found,
C

7.9
8.1
8.3
8.5
8.7
8.7
8.9
8.9
8.9
8.9
9.1
9.1
7.8
7.6
8.8

71 .0
71.5
71.9
72.6
72.8
73.4
73.5
73.1
73.3
73.2
73.6
73.6
75.6
75.0
74.4

%-H

8.0
8.2
8.2
8.3
9.1
8.7
8.9
8.8
8.9
9.0
9.6
9.0
8.0
7.7
9.1

Molar
uotencva

2.9
34
240
20
30
36
150
110
0
15

1.

dation of the quaternary salts proceeded very readily

to give the expected methine bases XXI.
Nomenclature. The systematic nomenclature for
the bases in this series, based on the 6,14-endo-ethenotetrahydrothebaine system, is cumbersome and, since
many degradation and rearrangement products of
thebaine, codeine, and morphine already have simple
trivial names, a simpler system, based on a trivial name
for a key intermediate, would be an advantage. The
trivial name nepenthone was assigned to the phenyl
ketone I (R = Ph) in order to facilitate the naming of
derivatives. The intermediates that have been most
widely used in this work are the aldehyde I (R = H)
and the ketones I (R = Me and Ph) and of these the
ketone I (R = Me) is much the most actike as an analgesic and gices rise to a kery wide series of alcohols of
structure I1 (R = Me) of high activity. These alcohols
are more easily prepared and of much greater pharmacological interest than the corresponding bases I1 (R
# Me). Accordingly, a tricial name has been assigned
to the ketone I (R = Me). This ketone is the adduct
of thebaine and methyl vinyl ketone and by a suitable
selection of syllables from the names of these compounds the name rheciriorie emerges for the ketone I
(R = Me). The related secondary alcohol I1 (R =
Me, R ' = H) then becomes thecznoI, and the other
bases in the series I1 (R = Me), being obviously homolog of I1 (R = Me, R ' = H), may be named as alkylthevinols, e.g., the alcohol 11 (R = Me, R ' = n-Pr)
beconiespropj,/thecinoi and I1 (R = Me, R' = CH2CH2Ph) becomes plieriethq.lthecirio1.
As will be seen in the following paper, most of the
alcohols of the series I1 have been demethylated to
phenolic 3-hydroxy analogs, and bases of this series
corresponding to those of structure I1 (R = Me),
being derivatives of tetrahydrooripavine rather than
tetrahydrothebaine, can be termed alkylorvinols, e.g.,
the 3-hydroxy analog of the base I1 (R = Me, R' =
cyclohexyl) would be cjdohexyiorcinol.
The acid I (R = OH), being an oxidized form of
thevinone, can be named thecitioic acid and the ester
I (R = OEt) then becomes ethyl theoinoate and the
acid chloride I (R = Cl) thecinoyl chloride. (The
term thevinic acid is avoided as this leads to the acid
chloride being named thevinyl chloride, which should
be reserved for the halide corresponding to thevinol.)
Journal of the American Chemical Society 1 89:13

Since a series of 6,14-ethano alcohols XIX derived

from the ketone XX is known, this last base can be
termed hydrothevinone and the alcohols thus become
alkylhydrotheuinols, or hydroorvinols after O-demethylation. Relatively simple extensions of this nomenclature permit rational names to be assigned to other
bases resulting from transformations of the ketone
I (R = Me) and the alcohols I1 (R = Me), and these
will be discussed where necessary in subsequent publications.
Experimental Section
Examples only of representative Grignard reactions and reductions are given in this section t o show the general processes used.
7a-(l-Hydroxy-l-methylethyl)-6,14-endo-ethenotetrahydrothebaine (19-Methylthevinol) (11, R = R ' = Me). a. A solution of
7a-acetyl-6,14-endo-ethenotetrahydrothebaine(thevinone) (I, R
= Me) (10 g) in dry ether (500 ml) or in dry benzene (50 ml) has
added slowly with vigorous stirring to a refluxing solution of methylmagnesium iodide, prepared from magnesium (1.67g) and methyl
iodide (9.9 g) in ether (100 ml), and the mixture was stirred and
heated under reflux for 2 hr. The mixture was then shaken with
aqueous ammonium chloride, and the organic layer was separated,
dried, and evaporated, leaving a crystalline base (10 g), which was
recrystallized from ethanol. The base was obtained in this way as
plates, mp 166".
Anal. Calcd for C24H31N01: C, 72.5; H, 7.9. Found: C,
72.5; H, 7.7.
b. 6,14-endo-Etheno-7a-ethoxycarbonyltetrahydrothebaine
(ethyl thevinoate) (I, R = OEt) (10 g) was extracted from a Soxhlet
extractor into a boiling stirred solution of methylmagnesium iodide
(from 1.67 g of magnesium and 9.9 g of methyl iodide) in ether
(100 ml). The mixture was boiled under reflux for 3 hr, and the
product isolated as in a above, when it was obtained (9.8 g) as
white prisms, mp 166", alone or mixed with material prepared
from the ketone.
7~-(l-Hydroxy-l-methylethyl)-6,14-er2do-ethenotetrahydrothebaine (19-Methyl-P-thevinol) (C-7 Epimer of 11, R = R ' = Me).
a. A solution of 7P-acetyl-6,14-endo-ethenotetrahydrothebaine
(0.5g) in ether (100 ml) was added to a stirred refluxing solution of
methylmagnesium iodide (from 0.17 g of magnesium and 1 g of
methyl iodide), and the mixture was boiled under reflux for 1 hr.
Isolation of the product in the usual way afforded a mixture of two
nonketonic products. These were separated on thick alumina
plates, and the base, having the greater Rfvalue, was obtained as
prisms, mp 190",on recrystallization from ethanol. It was identified as the alcohol epimeric at c-7with I1 (R = R' = Me) by its
nmr and infrared spectra, which were very similar to but not identical with those of I1 (R = R1 = Me).
Anal. Calcd for C2,H3,NO4: C, 72.5; H, 7.9. Found: C,
72.5; H,7.7.
The second product, of lower R f value, was phenolic and has
been identified as a product of base-catalyzed rearrangement of the

June 21, 1967

3279
to a stirred solution of methylmagnesium iodide (from 2 g of magparent ketone followed by Grignard reaction and is described in
nesium and 6 ml of methyl iodide) in ether (150 ml), and the mixture
detail in a later paper.6b
was boiled under reflux for 1 hr. Isolation of the product in the
Reduction of 7~~-Acetyl-6,14-endo-ethenotetrahydrothebaine
(Theusual way afforded 10.1 g of a base containing about 10% of the
vinone) (I, R = Me). a. The ketone I (R = Me) (10 g) was boiled
alcohol I1 (R = Me, R' = n-Pr). After several recrystallizations
with aluminum isopropoxide (10 g) and 2-propanol (100 ml) with
from methanol the alcohol I1 (R = n-Pr, R' = Me) was obtained
slow distillation of the solvent through a 36-plate fractionating
almost pure, as prisms, mp 144-145", and a pure specimen, mp
column until the distillate no longer gave a precipitate with a solution
148-149", for spectral studies was obtained by layer chromatoof 2,4-dinitrophenylhydrazinein aqueous hydrochloric acid. On
graphic separation on alumina.
completion of the reaction, the mixture was evaporated to small bulk
Anal. Calcd for C26H35N04:C, 73.3; H , 8.2. Found: C,
and poured into dilute hydrochloric acid. The acid solution was
73.2; H , 8.4.
saturated with potassium sodium tartrate and basified with am7~-(1-(R)-Hydroxy-l-methyIpropyl)-6,14-eildo-ethenotetrahydromonia, and the precipitated base was isolated by ether extraction,
thebaine (19-ethylthevinol) (11, R = Me, R ' = Et) was obtained
when the carbinol I1 (R = H , R' = Me) was obtained as a viscous
gum that was crystallized from aqueous methanol, being then obby the above general method from the ketone I (R = Me) and ethylmagnesium bromide as prisms, mp 74", with resolidification and
tained as white prisms, mp 78-80", raised to 82" by further recrysfin2 melting at 135".
tallization from aqueous methanol or ether at low temperatures.
A m l . Calcd for C23H29N04: C, 72.1: H , 7.6. Found: C,
Anal. Calcd for CW,HHNOI:
C. 73.1: H , 8.1. Found: C.
.. ..
.
72.0; H , 7.5.
72.9; H, 8.1.
Thin layer chromatographic studies showed that the base, mp
It was also obtained by the reduction of the vinylcarbinol I1
78-80", first obtained contained about 5 of the isomeric carbinol
(R = Me, R' = CH=CH2); see below.
I1 (R = Me, R ' = H), which is the main product of Grignard re7cu-(l-(S)-Hydroxy-l-methylpropyl)-6,14-end~-ethenotetrat1yduction of the ketone.
drothebaine (11, R = Et, R' = Me) was prepared by the general
The 0-formyl ester was prepared by heating the alcohol with
method from the ketone I (R = Et) and methylmagnesium iodide,
9 8 - 1 0 0 z formic acid at 100" for 1 hr and was obtained as plates,
when it was obtained as prisms, mp 165".
mp 110",from aqueous methanol.
Anal, Calcd for C25Hj3N04: C, 73.1; H, 8.1. Found: C,
A m / . Calcd for C D ~ H ~ ~ NC,O 70.1;
~ : H, 7.1. Found: C,
72.9; H, 8.2.
70.3; H , 7.2.
It was also obtained by the reduction of the acetylenic carbinol
The 0-acetyl ester, prepared from the alcohol and acetic anhydride
I1 (R = C=CH, R ' = Me); see below.
in pyridine, was obtained as plates, mp 170",from aqueous ethanol.
7cu-(l-(R-Hydroxy-l-methylprop-2-enyl)-6,14-endo-ethenotetraA m / . Calcd for CZjH31NOj: C, 70.7; H, 7.3. Found: C,
hydrothebaine (19-Vinylthevinol) (11, R = Me, R' = CH=CHy).
70.9; H , 7 . 5 .
A solution of 7~~-acetyl-6,14-endo-ethenotetrahydrothebaine
(I, R
b. The ketone I (R = Me) (10 g) was boiled under reflux in
= Me) (19 g) in dry tetrahydrofuran (30 ml) was added to a refluxmethanol (50 ml) with sodium borohydride (1 g) for 30 min. The
ing solution of vinylmagnesium bromide (from 3.0 g of magnesium
solution was concentrated by evaporation and poured into water
and 13.4 g of vinyl bromide) in tetrahydrofuran, and the mixture
and the precipitated base was isolated by ether extraction, when it
was boiled under reflux for 2 hr. Saturated aqueous ammonium
was obtained as a viscous gum, shown by thin layer chromatography
chloride was added, and the organic layer was separated, dried,
to consist of an approximately 1 : l mixture of the products of
and evaporated. The residual brown gum was crystallized from
Meerwein-Pondorff and Grignard reduction of the ketone.
methanol when the alcohol was obtained as white prisms, mp 155 '.
7cu-(l-(R)-Hydroxy-l-methylbutyl)-6,14-e~~do-ethenotetrahydroAnal. Calcd for C25H317d04: C, 73.3; H, 7.6. Found: C,
thebaine (19-Propylthevinol) (11, R = M e , R' = n-Pr)a nd Grignard
73.3; H , 7 . 6 .
Reduction of the Ketone I (R = CH,). 7cu-Acetyl-6,14-endo-ethenoReduction. The alcohol I1 (R = Me, R ' = CH=CH*) ( 5 g) in
tetrahydrothebaine (I, R = CHI) (50 g) in dry benzene (250 ml) was
ethanol (100 ml) was shaken under hydrogen at 22" (750 mm) in the
added to a vigorously stirred refluxing solution of n-propylmagpresence of platinum oxide (100 mg). Hydrogen (300 ml) was abnesium iodide (from 8.35 g of magnesium and 58.5 g of l-iodoprosorbed over 30 min, after which reduction ceased. Filtration and
pane) in ether (500 ml), and the mixture was boiled under reflux for
evaporation of the solution gave 5.0 g of material which on crystal2 hr. The product, isolated in the usual way, was a viscous gum
lization from ethanol gave prisms, mp 74 and 135', unaltered on
which crystallized on trituration with methanol (100 ml). The solid
mixing with the alcohol I1 (R = Me, R' = Et), obtained from the
was collected and recrystallized from ethanol, when the alcohol
action of ethylmagnesium bromide on the ketone I (R = Me).
I1 (R = Me, R ' = u-Pr) was obtained as white prisms, mp 176"
The infrared spectra and chromatographic behavior on alumina
(24.0 g).
plates of the bases from the two sources were also identical.
A d . Calcd for C26H35N04:C, 73.3; H , 8.2. Found: C,
7cu-(l-(S)-Hydroxy-l-methylprop-2-ynyl)-6,14-e~1~o-ethenote~ra73.2; H, 8.2.
thebaine (19-Ethynylthevinol) (11, R = C=CH, R' = Me). 7aThe mother liquors were diluted with methanol (50 mi) and water
Acetyl-6,14-endc-ethenotetrahydrothebaine
(I, R = Me) (38 g) in
was added until precipitation of gummy material began. The
dry tetrahydrofuran (200 ml) was added with stirring to a solution
solution was allowed to stand for 15 min, decanted from the gummy
of lithium acetylide-ethylenediamine complex (10 g) under an atmaterial, and then kept in the refrigerator, when the Grignard remosphere of argon. The mixture was stirred at 3 5 " for 3 hr and
duction product, 7 4 l-(S)-hydroxyethyl)-6,14-e11do-ethenotetrahy- poured into water (200 ml). The mixture was extracted three
drothebaine (thevinol) (11, R = Me, R ' = H ) (12 g) was obtained
times with ether, and the combined extracts were dried and evapas needles, mp 76-78", raised to 81" on recrystallization from
orated. The residue crystallized in part on trituration with methaqueous methanol.
anol (20 ml), and the solid (10.5 g) was collected and recrystallized
A m / . Calcd for C23H2'JN04:C, 72.1; H , 7.6. Found: C,
from methanol when the alcohol I1 (R = C=CH, R' = Me) was
71.8; H , 8.0.
obtained as prisms, mp 185-186".
The 0-formyl ester, prepared by heating the secondary alcohol
Anal. Calcd for C25H29N04:C, 73.7; H , 7.1. Found: C,
with 9 8 - 1 0 0 z formic acid at 100"for 1 hr, was obtained as prisms,
73.6; H, 7.2.
mp 148", from aqueous methanol.
A further 4.1 g of material, mp 183-184", was obtained on corLA/ial. Calcd for C24H2DNOi.0.5H20:
C, 68.6; H, 7.2. Found:
centration of the mother liquors. Final evaporation of these
C, 68.7; H, 7.3.
liquors afforded a gum shown by thin layer chromatography to
The 0-acetyl ester, prepared from the alcohol, acetic anhydride,
consist of an approximately 1 : 1 mixture of the above base and a
and pyridine, was obtained as prisms, mp 120, from aqueous
second compound, presumably the diastereoisomeric alcohol I1
methanol.
(R = Me, R ' = C=CH), since the infrared spectrum of the mixture
Anal. Calcd for C25H3,NOe: C, 70.7; H, 7.3. Found: C,
was almost identical with that of the pure base, mp 185-186".
70.8; H, 7.5.
Reduction. The acetylenic alcohol I1 (R = C=CH, R' = Me)
A third base has been isolated from the residues of separation
(4.0 g) was hydrogenated over platinum oxide (100 mg) in ethanol at
22" (760 mm). Hydrogen (449 mi, 2 moles) was absorbed over 20
of the Grignard reduction product. This was a phenol, mp 201203 ', and is a product of base-catalyzed rearrangement of the parent
min, and isolation of the product afforded the alcohol I1 (R = Et,
ketone followed by normal Grignard reaction with propylmagR' = Me), mp 165", identical in melting point, mixture melting
nesium iodide; it is described fully in a later paper.6b
point, infrared absorption, and RI value with the product of the
7cu-(l-(S)-Hydroxy-l-methylbutyl)-6,14-e~~do-ethenotetrahydro- action of methylmagnesium iodide on the ketone I (R = Et).
thebaine (11, R = n-Pr, R' = Me). 7cu-Butyryl-6,14-erzdo-ethenoStudy of the Stereochemistry at C-19 of the Alcohols I1 (R = H ,
tetrahydrothebaine (I, R = n-Pr) (15 g) in ether (500 ml) was added
R' = M e and R = Me, R' = H). A so!ution of 7a-(l-(R)-hydroxy,

Bently, Hardy, Meek

1 Alcohols Derived from 6,14-Ethano Analogs

3280
ethyl)-6,14-eiido-ethenotetrahydrothebaine (11, R

= H, R ' =
Me) ( 5 g) and phenylglyoxalyl chloride (6 g) in pyridine (12 ml)
was kept at room temperature overnight. Ice water was then
added until separation of solid matter occurred. The solid was isolated by ether extraction, and the viscous gum so obtained was
crystallized by trituration with methanol. The solid was collected
(3.5 g) and recrystallized from methanol when the phenylglyoxalyl
ester was obtained as off-white plates, mp 206".
A d . Calcd for CJ-I33NO6.H?O: C, 69.85; H, 6.7. Found:
C, 70.0; H , 7.0.
A solution of methylmagnesium iodide (from 0.95 g of magnesium
and 25 ml of methyl iodide) in ether (30 ml) was added to a solution
of the phenylglyoxalyl ester ( 5 g) in dry benzene (100 ml), and the
mixture was kept at room temperature for 3 hr and then boiled
under reflux for 3 hr. The mixture was poured into aqueous ammonium chloride; the organic layer was separated and the aqueous
layer extracted twice with chloroform. The combined etherbenzene and chloroform solutions were evaporated, and the residue
was boiled under reflux with 5 % methanolic potassium hydroxide
(200 ml) for 5 hr. Most of the methanol was evaporated, and the
mixture was diluted with water (200 ml) and extracted four times
with ether to remove the organic base. The aqueous layer was
acidified with hydrochloric acid and extracted continuously with
ether for 3 days. The ether extract on evaporation afforded a gum
from which atrolactic acid, mp 114-115", [ ~ ] * O D +4.8", was obtained as white needles on extraction with light petroleum (bp
80-100").
Repetition of the above reactions using 7a-(l-(S)-hydroxyethyl)6.14-er?do-ethenotetrahydrothebaine(11, R = Me, R 1 = H) as
starting material afforded the phenylglyoxalyl ester as prisms, mp
96 and 170", and atrolactic acid, mp 114-115", [ O ] * ~ D-5.4".
Am[. Calcd for C31H33N06.H20:C, 69.85; H , 6.7. Found:
C, 70.2; H, 7.0.
7a-Acetgl-6,14-e/ido-ethanotetrahydrothebaine
(Dihydrothevinone)
(XX). 7a-Acetyl-6,14-er?do-ethenotetrahydrothebaine
(I, R = Me)
(5 g) in ethanol (200 ml) was shaken with 10 % palladium on charcoal
(0.5 g) under hydrogen at 58 psi at 50" for 10 hr. The mixture was
filtered from the catalyst and evaporated. The residue was crystal(3.8 g)
lized from ethanol when the 6,14-endo-ethano-7a-ketone
was obtained as white prisms, mp 134-136", urnax 1710 cm-'.
A/ia/. Calcd for C?3H?,N04: C, 72.0; H, 7.6. Found: C,
71.6; H, 7.6.
7~-Acetyl-6,14-endo-ethanotetrahydrothebaine
(P-Dihydrothevinone) ((2-7 Epimer of XX). 7/3-Acetyl-6,14-endo-ethenotetrahydrothebaine (0.38 g) was hydrogenated over 10% palladium on charcoal (0.20 g) in ethanol (100 ml) at 22" (755 mm). Hydrogen (22
ml) was absorbed over 7 min. The solution was filtered and
evaporated, and the residue was crystallized from ethanol when the
6,14-ethano-7P-ketonewas obtained as prisms, mp 166".
A/ra/. Calcd for C 2 3 H ~ B N 0 4C,
: 72.0; H, 7.6. Found: C,
71.8; H , 7.6.
6,14-e/ido-Ethano-7a-formyltetrahydrothehaine
(XX, CH3 = H).
6.14-c~~rdo-Etheno-7a-formyltetrahydrothebaine
(I, R = H) (1.84
g) was hydrogenated over 10% palladium on charcoal (0.3 g) in
ethanol (50 ml) at 22" (760 mm). Hydrogen (1 12 ml) was absorbed
over 2.5 hr. The isolated product was crystallized from ethanol
when the 6.14-endo-ethano-7a-aldehydewas obtained as prisms,
nip 98", vmnx 1740 cm-l.
Ami/, Calcd for C22H?;N04: C, 71.5; H , 7.4. Found: C,
71.2; H, 7.2.
6,14-endo-Ethano-70-(l-(R)-hydroxyethyl)tetrahydrothebaine
(XIX, R = H,R' = Me). 6,14-ertdo-Etheno-7cu-(l-(R)-hydroxy-

ethy1)tetrahydrothebaine (11, R = H, R ' = Me) (25 g) (from the

Meerwein-Pondorff reduction of the ketone I, R = Me) was hydrogenated at 22" (760 mm) in ethanol (100 ml) over 10 % palladium
on charcoal (1 g). Hydrogen (1500 ml) was absorbed over 50
min. The product was isolated as prisms, mp 49-51 O, from aqueous
methanol.
Anal. Calcd for C23H31N04:C, 71.6; H, 8.1. Found: C,
71.5; H, 8.2.
The 0-p-toluenesulfonate was obtained as prisms, mp 157",
from benzene-methanol.
Anal. Calcd for C30H3iN06S.0.5H20: C, 65.6; H, 7.0;
S,5.8. Found: C,65.3; H,7.0; S, 5.7.
The diastereoisomeric alcohol 11 (R = Me, R ' = H), from the
Grignard reduction of the ketone I (R = Me), was resistant to
hydrogenation under the above conditions and at temperatures up
to 60".
6,14-e~ido-Ethano-7a-(l-hydroxy-l-methylethyl)tetrahydrothebaine (Dihydro-19-methylthevinol) (XIX, R = R ' = Me). a.
6,14-endo-Etheno-7a - (1-hydroxy - 1- methylethy1)tetrahydrothebaine
(11, R = R ' = Me) (40 g) was hydrogenated in ethanol (300
ml) over W4 Raney nickel (10 g) at 16&165" (164-182 atm)
for 4 hr. The solution was filtered and concentrated to yield the
6,14-ethano alcohol as white prisms, mp 142", after recrystallization
from ethanol.
A d . Calcd for C24H33N04:C, 72.2; H, 8.3; N, 3.5. Found:
C, 71.8; H, 8.2; N, 3.5.
b. The same base was obtained by the action of methylmagnesium iodide (from 0.83 g of magnesium and 5.2 g of methyl iodide)
on 7a-acetyl-6,14-erzdo-ethanotetrahydrothebaine(dihydrothevinone) (4.8 g) in ether solution.
Hofman Degradation of the Alcohols I1 (R = Me,R' = rz-Pr and
R = Me, R ' = Ph). 19-Propylthevinol (11, R = Me, R' = n-Pr)
and 19-phenylthevinol(II, R = Me, R 1= Ph) (2 g) were separately
boiled under reflux with methyl iodide (10 ml) and acetone (20 ml)
for 7 days. The solvent was evaporated, and the residue was
recrystallized from ethanol to give 19-propylthevinol methiodide
(white prisms, mp 188-190". Anal. Calcd for C ? ; H ~ R N O ~ I .
0.5H20: C, 56.3; H, 6.8. Found: C, 56.4; H, 5.8) and 19phenylthevinol methiodide (white prisms, mp 194-196'. A d .
Calcd for C30H36N041.0.5H20:
C, 59.0; H, 6.1. Found: C,
58.7; H , 6.1).
The methiodides (1 g) were degraded by boiling under reflux with
20% aqueous potassium hydroxide for 15 min. The solution was
diluted and the product collected at the pump and recrystallized
from aqueous ethanol to give 19-propylthevinol methine (XXI,
R ' = iz-Pr; white needles, mp 90-95", , , ,A
230, 279, 308, 318
mp (emax 12,000, 7000, 3000, 2300). A/ia/. Calcd for C2;H3;N04.
H 2 0 : C, 70.9; H, 8.5. Found: C, 71.2; H, 8.3) and 19-phenyl279
thevinol methine (XXI, R ' = Ph, white plates, mp 160",, , ,A
and 310 mp (emsx 8050 and 3500). Anal. Calcd for CaoH30N04.
H 2 0 : C, 73.4; H, 7.5. Found: C, 73.2; H, 7.6).

Acknowledgments. The authors wish to thank Dr.

D. E. Webster of the University of Hull, England, for
the determination of nmr spectra and the following for
experimental assistance: Dr. J. D. Bower, Dr. A. C.
B. Smith, Mr. C. Carter, Mr. J. Fulstow, Mr. P. J.
Grayson, Mr. G. Lee, Mr. G. Mellows, Mr. J. F. Saville,
Mr. J. K. Saville, Mr. T. M. Sutton, Mr. J. Tattersall,
Mrs. E. M. Walker, and the late Mr. S. R. Duff.

Journal of the American Chemical Society / 89:13 / June 21, 1967